Domagala J M, Gogliotti R, Sanchez J P, Stier M A, Musa K, Song Y, Loo J, Reily M, Tummino P, Harvey P, Hupe D, Sharmeen L, Mack D, Scholten J, Saunders J, McQuade T
Department of Chemistry, Parke Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
Drug Des Discov. 1997 May;15(1):49-61.
Substituted 2,2'-dithiobisbenzamides and 2-benzisothiazolones were prepared and shown to possess low microM activity with high therapeutic indices against HIV-1, HIV-2 and SIV in cell culture. The mechanism of antiviral action was determined to be directed toward the nucleocapsid protein (NCp7), which contains two zinc fingers and plays vital roles in the viral life cycle. The "active sulfides" of this study cause the extrusion of zinc from these zinc fingers. Structure-activity relationships of the 2,2'-dithiobisbenzamides reveal that the disulfide bond and the ortho benzamide functional groups are essential for activity, with the best compounds having a carboxylic acid, carboxamide, or sulfonamide substituent. The 2-benzisothiazolones are formed from the disulfides both chemically and in vivo and their SAR mimics that of the 2,2'-dithiobisbenzamides. The antiviral activity of the disulfides may require cyclization to the isothiazolones. Two agents, PD 159206 and PD 161374, which showed good antiviral activity, physical properties, and excellent pharmacokinetics in mice, were selected for advanced studies.
制备了取代的2,2'-二硫代双苯甲酰胺和2-苯并异噻唑酮，并证明它们在细胞培养中对HIV-1、HIV-2和SIV具有低微摩尔活性和高治疗指数。抗病毒作用机制被确定为针对核衣壳蛋白（NCp7），该蛋白含有两个锌指，在病毒生命周期中起重要作用。本研究中的“活性硫化物”会导致锌从这些锌指中挤出。2,2'-二硫代双苯甲酰胺的构效关系表明，二硫键和邻位苯甲酰胺官能团对活性至关重要，最佳化合物具有羧酸、羧酰胺或磺酰胺取代基。2-苯并异噻唑酮可通过化学方法和体内由二硫化物形成，其构效关系与2,2'-二硫代双苯甲酰胺相似。二硫化物的抗病毒活性可能需要环化形成异噻唑酮。选择了两种在小鼠中显示出良好抗病毒活性、物理性质和优异药代动力学的药物PD 159206和PD 161374进行进一步研究。
